The broad, long-term objective of this component is to use modern methods in molecular and structural biology to develop a detailed understanding of the structure and function of the low density lipoprotein (LDL) receptor (LDLR), and to relate this understanding to the existing, large human- genetics database (e.g., LDLR mutations in familial hypercholesterolemia (FH)). Despite the wealth of information about the human genetics and cell biology of LDLR, our understanding of this receptor in terms of structure and function is relatively primitive. We will interact extensively with component III, which will facilitate our analysis of LDLR by providing novel mutants and transfected cell lines. The specific aims of this component are: (1) To understand the structural basis of the binding of lipoproteins by LDLR, and to put the large number of mutations that affect binding, and thereby cause FH, into a structural and mechanistic perspective. ] (2) To understand the structural basis of the pH switch for ligand release by LDLR in acidic endosomes, and the mechanism by which some mutations disable this pH-0switch, resulting in FH. (3) To understand the structural basis for the "lipid activation" of apolipoprotein E (apoE), a high affinity ligand of LDLR and the LDLR- related protein (LRP, a chylomicron receptor).